This invention relates to the chemotherapy of bacterial infections in mammalian subjects. More particularly, it relates to sparingly water-soluble salts of the beta-lactamase inhibitor penicillanic acid 1,1-dioxide, and their use in conjunction with beta-lactam antibiotics in the chemotherapy of bacterial infections in mammals.
One of the most well-known and widely used of the classes of antibacterial agents is the class known as the beta-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (beta-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the beta-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given beta-lactam antibiotic results because the microorganism produces a beta-lactamase. The latter substances are enzymes which cleave the beta-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit beta-lactamases, and when a beta-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. One useful beta-lactamase inhibitor is penicillanic acid 1,1-dioxide, the compound of the formula I: ##STR1##
U.S. Pat. No. 4,234,579 describes the preparation of penicillanic acid 1,1-dioxide, and methods for its use as a beta-lactamase inhibitor in combination with beta-lactam antibiotics. Additionally, U.S. Pat. No. 4,234,579 discloses salts of penicillanic acid 1,1-dioxide, including amine salts. However, the amine salts disclosed in U.S. Pat. No. 4,234,579 are relatively soluble in water, and they are rapidly excreted from the mammalian subject after parenteral administration. It has now been found that certain amine salts of penicillanic acid 1,1-dioxide are sparingly soluble in water, and after parenteral administration to a mammalian subject they give prolonged blood levels of penicillanic acid 1,1-dioxide. These sparingly soluble salts of penicillanic acid 1,1-dioxide are the 1:2 N,N'-dibenzylethylenediamine salt, the N-benzyl-2-phenylamine salt and the dibenzylamine salt.
The 1:2 N,N'-dibenzylethylenediamine, the N-benzyl-2-phenylethylamine and the dibenzylamine salts of several penicillin antibiotics e.g. benzylpenicillin, have been prepared. See further: U.S. Pat. Nos. 2,627,491 and 2,585,432 and British Pat. No. 732,559.